The demand for enantiomerically pure compounds has grown rapidly in recent years. One important use for such chiral, non-racemic compounds is as intermediates for synthesis in the pharmaceutical industry. For instance, it has become increasingly clear that enantiomerically pure drugs have many advantages over racemic drug mixtures. The advantages of enantiomerically pure compounds (reviewed in, e.g., Stinson, S. C., Chem Eng News, Sept. 28, 1992, pp. 46-79) include fewer side effects and greater potency in many cases.
Traditional methods of organic synthesis have often been optimized for the production of racemic materials. The production of enantiomerically pure material has historically been achieved in one of two ways: the use of enantiomerically pure starting materials derived from natural sources (the so-called xe2x80x9cchiral poolxe2x80x9d); or the resolution of racemic mixtures by classical techniques. Each of these methods has serious drawbacks, however. The chiral pool is limited to compounds found in nature, so only certain structures and absolute configurations are readily available. Resolution of racemates often requires the use of resolving agents; this process may be inconvenient and is certain to be time-consuming. Furthermore, resolution often means that the undesired enantiomer is discarded, thereby wasting half of the material.
Cycloaddition reactions are powerful, frequently-exploited elements of the palette of transformations available to the synthetic organic chemist. There are numerous reasons for the importance of cycloaddition reactions, inter a/ia: 1) they are concerted reactions; 2) their products are significantly more complex than the required starting materials; 3) the relative simplicity and synthetic accessibility of the required starting materials; and 4) they are capable of generating a number of stereocenters in a single operation. The first of these points is tremendously important because concerted reactions transmit to their products in well-understood ways the stereochemical information contained in their starting materials.
The synthetic utility of cycloaddition reactions in which one of the reactants is a carbonyl group or analogue thereofxe2x80x94termed xe2x80x9cHeteroxe2x80x9d-cycloadditionsxe2x80x94has been further expanded by progress in the development of asymmetric catalysts for these reactions. The Hetero-Diels-Alder reaction is perhaps the best example of a cycloaddition reaction whose utility has been has been augmented by research directed at the development of asymmetric catalysts (for a review, see: Danishefsky Chemtracts. Organic Chemistry 1989, 273). Catalysts comprising a transition metal ion and a chiral, non-racemic ligand have been reported to render enantioselective various Hetero-Diels-Alder cycloadditions; these reactions gave products in good to excellent enantiomeric excess (for leading references, see: Danishefsky and DeNinno, Angew. Chim., Intl. Ed. Engl. 1987, 26, 15-23; Corey and Loh, J. Am. Chem. Soc., 1991, 113, 8966-8967; Yamamoto et al., J. Org. Chem., 1992, 57, 1951-1952; Keck et al., J. Org. Chem., 1995, 60, 5998-5999; and Ghosh et al., Tetrahedron Lett. 1997, 38, 2427-2430).
The cyclohexene ring generated in a Diels-Alder reaction can be incorporated without further modification into biologically-active natural products, drug candidates, and pharmaceuticals. Additionally, the newly-formed cyclohexene ring may serve as a starting point for further synthetic transformations. For example, the A, B, and C rings of the steroid skeleton are functionalized cyclohexane rings; a number of routes to steriods based on the Diels-Alder reaction have been reported. The olefin in the cyclohexene derived from a Diels-Alder reaction can serve as a functional handle for subsequent transformations. The Diels-Alder reaction tolerates a wide range of xe2x80x9cspectatorxe2x80x9d functionalityxe2x80x94functionality not involved in, or affected by, the reaction conditionsxe2x80x94which can serve as reactive sites in subsequent transformations. Finally, the so-called Hetero-Diels-Alder reaction provides access to unsaturated six-membered heterocycles.
In one aspect of the present invention, there is provided a process for enantioselective chemical synthesis which generally comprises reacting a diene and an aldehyde in the presence of a non-racemic chiral catalyst to produce a enantiomerically enriched dihydropyran product. The diene substrate comprises a 1,3-diene moiety, the dienophile comprises a single reactive xcfx80-bond, and the chiral catalyst comprises an asymmetric tetradentate or tridentate ligand complexed with a transition metal ion. In the instance of the tetradentate ligand, the catalyst complex has a rectangular planar or rectangular pyrimidal geometry. The tridentate ligand-metal complex has a trigonal pyrimidal or planar geometry. In a preferred embodiment, the ligand has at least one Schiff base nitrogen complexed with the metal core of the catalyst. In another preferred embodiment, the ligand provides at least one stereogenic center within two bonds of a ligand atom which coordinates the metal.
In general, the metal atom is a main group metal or transition metal from Groups 3-12 or from the lanthanide series, and is preferably not in its highest state of oxidation. For example, the metal can be a late transition metal, such as selected from the Group 5-12 transition metals. In certain embodiments, the metal atom is selected from the group consisting of Na, K, Rb, Mg, Ca, Sr, B, Al, Ga, In, Si, Ge, and Sn. In certain embodiments, the metal atom is selected from the group consisting of Co, Cr, Mn, V, Fe, Mo, W, Ru and Ni.
Exemplary diene substrates for the subject reaction include 1,3-dienes in which any or all of the heavy atoms comprising the backbone of said 1,3-diene are chosen from the set containing C, N, O, S, and P.
In preferred embodiments, the subject transformation can be represented as follows: 
wherein
Y represents O, S, or NR7;
R1, R2, R3, R4, R5 and R6 each independently represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R8;
any two or more of the substituents R1, R2, R3, R4, R5 and R6 taken together may form a carbocylic or heterocyclic ring having from 4 to 8 atoms in the ring structure;
R8 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and
m is zero or an integer in the range of 1 to 8.
In certain embodiments, R1, R2, R3, and R4 are chosen such that the substrate has a plane of symmetry.
Exemplary dienophile substrates for the subject reaction include aldehydes, ketones, esters, amides, carbonates, thioaldehydes, thioamides, thiocarbonates, lactones, lactams, thiollactones, thiolactams, imines, oximes, hydrazones, thionoesters, thioesters, dithioesters, thionolactones, thiolactones, dithiolactones, phosphorus ylides, thioketones, acid halides, anhydrides, imines, iminium ions, imines, oximes, oximes, hydrazones, nitroso-containing compounds, nitro-containing compounds, compounds containing a phosphorus-oxygen xcfx80-bond, and compounds containing a phosphorus-sulfur xcfx80-bond.
In a preferred embodiment, the method includes combining a diene, a dienophile, and a non-racemic chiral catalyst as described herein, and maintaining the combination under conditions appropriate for the chiral catalyst to catalyze an enantioselective cycloaddition reaction between the two substrates.
In certain embodiments, the chiral catalyst which is employed in the subject reaction is represented by the general formula: 
wherein
Z1, Z2, Z3 and Z4 each represent a Lewis base;
the C1 moiety, taken together with Z1, Z3 and M, and the C2 moiety, taken together with Z2, Z4 and M, each, independently, form a heterocycle;
R1, R2, Rxe2x80x21 and Rxe2x80x22 each, independently, are absent or represent a covalent substitution with an organic or inorganic substituent permitted by valence requirements of the electron donor atom to which it is attached;
R40 and R41 each independently are absent, or represent one or more covalent substitutions of C1 and C2 with an organic or inorganic substituent permitted by valence requirements of the ring atom to which it is attached;
any two or more of the R1, R2, Rxe2x80x21, Rxe2x80x22 R40 and R41 taken together may form a bridging substituent;
with the proviso that C1 is substituted at least once by R1, Rxe2x80x21 or R41, and C2 is substituted at least once by R2, Rxe2x80x22 or R40, and at least one of R1, Rxe2x80x21 and R41 is taken together with at least one of R2, Rxe2x80x22 and R40 to form a bridging substituent so as to provide Z1, Z2, Z3 and Z4 as a tetradentate ligand;
M represents the metal ion; and
A represents a counterion,
wherein each R1, R2, Rxe2x80x21, Rxe2x80x22 R40 and R41 are selected to provide at least one stereogenic center in the tetradentate ligand.
In exemplary embodiments, R1, R2, Rxe2x80x21 and Rxe2x80x22, independently, represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R8;
each R40 and R41 occuring in 100 independently represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R8;
R8 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle;
Z1, Z2, Z3 and Z4 are independently selected from the group consisting of nitrogen, oxygen, phosphorus, arsenic, and sulfur; and
m is zero or an integer in the range of 1 to 8.
For example, the catalyst can be represented by the general formula: 
wherein
the substituents R1, R2, Y1, Y2, X1, X2, X3 and X4 each, independently, represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R8;
any two or more of the substituents taken together may form a carbocycle or heterocycle ring having from 4 to 8 atoms in the ring structure;
with the proviso that at least one of R1, Y1, X1 and X2 is covalently bonded to at least one of R2, Y2, X3 and X4 to provide the xcex2-alkoxylimines to which they are attached as a tetradentate ligand, and at least one of Y1 and Y2 is a hydrogen;
R8 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle , or a polycycle;
m is zero or an integer in the range of 1 to 8;
M represents the metal; and
A represents a counterion,
wherein each of of the substituents R1, R2, Y1, Y2, X1, X2, X3 and X4, are selected such that the catalyst is asymmetric.
For example, a preferred class of catalysts are represented by the general formula: 
wherein
the B1 moiety represents a diimine bridging substituent represented by xe2x80x94R15xe2x80x94R16xe2x80x94R17xe2x80x94, wherein R15 and R17 each independently are absent or represent an alkyl, an alkenyl, or an alkynyl, and R16 is absent or represents an amine, an imine, an amide, a phosphoryl, a carbonyl, a silyl, an oxygen, a sulfur, a sufonyl, a selenium, a carbonyl, or an ester;
each of B2 and B3 independently represent rings selected from a group consisting of cycloalkyls, cycloakenyls, aryls, and heterocyclic rings, which rings comprising from 4 to 8 atoms in a ring structure;
Y1 and Y2 each independently represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R8,
R12, R13, and R14 each independently are absent, or represent one or more covalent substitutions of B1, B2 and B3 with halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R8, wherein R12 can occur on one or more positions of xe2x80x94R15xe2x80x94R16xe2x80x94R17xe2x80x94,
or any two or more of the R12, R13, R14, Y1 and Y2 taken together form a bridging substituent;
R8 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle , or a polycycle;
m is zero or an integer in the range of 1 to 8;
M represents a metal; and
A represents a counterion,
wherein R12, R13, R14, Y1 and Y2 are selected such that the catalyst is asymmetric.
In additional preferred embodiments, the catalyst is a metallosalenate catalyst represented by the general formula: 
wherein
each of the substituents R1, R2, R3, R4, R5, Y1, Y2, X1, X2, X3, X4, X5, X6, X7, and X8, independently, represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R8;
any two or more of the substituents taken together may form a carbocycle or heterocycle having from 4 to 10 atoms in the ring structure;
R8 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle;
m is zero or an integer in the range of 1 to 8;
M represents a metal; and
A represents a counterion; wherein if R5 is absent, at least one of R1 and R2 taken together with at least one of R3 and R4 forms a bridging substituent, and each of the substituents of 106 are selected such that the salenate is asymmetric.
Alternatively, the catalyst comprises a tridentate ligand, such as the catalyst represented by the general formula: 
wherein
Z1, Z2, and Z3 each represent a Lewis base;
the E1 moiety, taken with Z1, Z2 and M, and the E2 moiety, taken with Z2, Z3 and M, each, independently, form a heterocycle;
R80 and R81 each independently are absent, hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R8;
any two or more of the R80 and R81 substituents taken together may form a bridging substituent;
R8 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle;
m is zero or an integer in the range of 1 to 8;
M represents a metal; and
A represents a counteranion,
wherein the tridentate ligand is asymmetric.
In certain embodiments, the catalyst complex comprises a tridentate ligand and is represented by general structure 160: 
wherein
Z represents N, P or As;
X represents independently for each occurrence O, S, Se or ZR;
M represents a metal ion and the requisite number of counterions;
R represents independently for each occurrence hydrogen, alkyl, aryl, halo, acyl or aralkyl; or taken together any two instances of R on adjacent carbons may represent an optionally substituted ring consisting of 3-8 backbone atoms inclusive; said ring being saturated, unsaturated or aromatic; and said ring may be fused to another optionally substituted ring;
Rxe2x80x2 represents independently for each occurrence hydrogen, alkyl, aryl, halo, acyl or aralkyl; or taken together the two instances of Rxe2x80x2 may represent an optionally substituted ring consisting of 3-8 backbone atoms inclusive; said ring being saturated, unsaturated or aromatic; and said ring may be fused to another optionally substituted ring; and
one or both of the carbons bearing an instance of Rxe2x80x2 may be asymmetric.
In certain embodiments, the catalyst complex comprises a tridentate ligand and is represented by general structure 162: 
wherein
X represents independently for each occurrence O, S, Se or ZR1;
Z represents independently for each occurrence N, P or As;
M represents a metal ion and the requisite number of counterions;
R1 represents independently for each occurrence hydrogen, alkyl or aryl;
R2 represents independently for each occurrence hydrogen, alkyl or aryl; and taken together the two instances of R2 may represent an optionally substituted ring consisting of 3-8 backbone atoms inclusive; said ring being saturated, unsaturated or aromatic; and said ring may be fused to another optionally substituted ring;
R3 may be absent or present between one and four times inclusive;
R3 represents independently for each occurrence alkyl, aryl, aralkyl, halo, acyl, sulfonyl, xe2x80x94(C(R1)2)mCOR1, xe2x80x94(C(R1)2)mCO2R1, xe2x80x94(C(R1 )2)mNO2, xe2x80x94(C(R1)2)mS(O)nR1, xe2x80x94(C(R1)2)mOR1, xe2x80x94(C(R1)2)mN(R1)2;
n represents independently for each occurrence an integer in the range 0-3 inclusive;
m represents independently for each occurrence an integer in the range 0-8 inclusive; and
one or both of the carbons bearing an instance of R2 may be asymmetric.
The demand for enantiomerically pure compounds has grown rapidly in recent years. One important use for such chiral, non-racemic compounds is as intermediates for synthesis in the pharmaceutical industry. For instance, it has become increasingly clear that enantiomerically pure drugs have many advantages over racemic drug mixtures. The advantages of enantiomerically pure compounds (reviewed in, e.g., Stinson, S. C., Chem Eng News, Sept. 28, 1992, pp. 46-79) include fewer side effects and greater potency in many cases. As described herein, the present invention makes available methods and reagents for enantioselective synthesis involving cycloaddition reactions. The primary constituents of the method, set out in more detail below, are a chiral, non-racemic metal catalyst of particular tetradentate or tridentate geometry; a chiral or prochiral diene, and a chiral or prochiral dienophile; the diene and/or dienophile are chosen so that the outcome of the reaction is influenced by the presence of the aforementioned chiral, non-racemic catalyst.
I. Definitions
For convenience, certain terms employed in the specification, examples, and appended claims are collected here.
The term xe2x80x9cnucleophilexe2x80x9d is recognized in the art, and as used herein means a chemical moiety having a reactive pair of electrons. Examples of nucleophiles include uncharged compounds such as amines, mercaptans and alcohols, and charged moieties such as alkoxides, thiolates, carbanions, and a variety of organic and inorganic anions. Illustrative anionic nucleophiles include simple anions such as azide, cyanide, thiocyanate, acetate, formate or chloroformate, and bisulfite. Organometallic reagents such as organocuprates, organozincs, organolithiums, Grignard reagents, enolates, acetylides, and the like may, under approriate reaction conditions, be suitable nucleophiles. Hydride may also be a suitable nucleophile when reduction of the substrate is desired.
The term xe2x80x9celectrophilexe2x80x9d is art-recognized and refers to chemical moieties which can accept a pair of electrons from a nucleophile as defined above. Electrophiles useful in the method of the present invention include cyclic compounds such as epoxides, aziridines, episulfides, cyclic sulfates, carbonates, lactones, lactams and the like. Non-cyclic electrophiles include sulfates, sulfonates (e.g. tosylates), chlorides, bromides, iodides, and the like
The terms xe2x80x9celectrophilic atomxe2x80x9d, xe2x80x9celectrophilic centerxe2x80x9d and xe2x80x9creactive centerxe2x80x9d as used herein refer to the atom of the substrate which is attacked by, and forms a new bond to, the nucleophile. In most (but not all) cases, this will also be the atom from which the leaving group departs.
The term xe2x80x9celectron-withdrawing groupxe2x80x9d is recognized in the art and as used herein means a functionality which draws electrons to itself more than a hydrogen atom would at the same position. Exemplary electron-withdrawing groups include nitro, ketone, aldehyde, sulfonyl, trifluoromethyl, xe2x80x94CN, chloride, and the like. The term xe2x80x9celectron-donating groupxe2x80x9d, as used herein, means a functionality which draws electrons to itself less than a hydrogen atom would at the same position. Exemplary electron-donating groups include amino, methoxy, and the like.
The term xe2x80x9cdienexe2x80x9d refers to a molecule containing at least one pair of conjugated xcfx80-bonds. The individual xcfx80-bonds of the diene moiety may be between any two atoms drawn from the set composed of C, N, O, S, and P. The conjugated conjugated xcfx80-bonds of the diene must be capable of adopting the so-called s-cis conformation.
The term xe2x80x9cdienophilexe2x80x9d refers to a molecule containing at least one reactive xcfx80-bond. The reactive xcfx80-bond of the dienophile may be between any two atoms drawn from the set composed of C, N, O, S, and P. In preferred embodiments, exactly one of the atoms contained in the reactive xcfx80-bond is carbon.
The term xe2x80x9cring expansionxe2x80x9d refers to a process whereby the number of atoms in a ring of a cyclic compound is increased. An illustrative example of ring expansion is the reaction of epoxides with CO2 to yield cyclic carbonates.
The term xe2x80x9cmeso compoundxe2x80x9d is recognized in the art and means a chemical compound which has at least two chiral centers but is achiral due to the presence of an internal plane or point of symmetry.
The term xe2x80x9cchiralxe2x80x9d refers to molecules which have the property of non-superimposability of their mirror image partner, while the term xe2x80x9cachiralxe2x80x9d refers to molecules which are superimposable on their mirror image partner. A xe2x80x9cprochiral moleculexe2x80x9d is a molecule which has the potential to be converted to a chiral molecule in a particular process.
The term xe2x80x9cstereoisomersxe2x80x9d refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. In particular, xe2x80x9cenantiomersxe2x80x9d refer to two stereoisomers of a compound which are non-superimposable mirror images of one another. xe2x80x9cDiastereomersxe2x80x9d, on the other hand, refers to stereoisomers with two or more centers of dissymmetry and whose molecules are not mirror images of one another.
Furthermore, a xe2x80x9cstereoselective processxe2x80x9d is one which produces a particular stereoisomer of a reaction product in preference to other possible stereoisomers of that product. An xe2x80x9cenantioselective processxe2x80x9d is one which favors production of one of the two possible enantiomers of a reaction product. The subject method is said to produce a xe2x80x9cstereoisomerically-enrichedxe2x80x9d product (e.g., enantiomerically-enriched or diastereomerically-enriched) when the yield of a particular stereoisomer of the product is greater by a statistically significant amount relative to the yield of that stereoisomer resulting from the same reaction run in the absence of a chiral catalyst. For example, a reaction which routinely produces a racemic mixture will, when catalyzed by one of the subject chiral catalysts, yield an e.e. for a particular enantiomer of the product.
The term xe2x80x9cregioisomersxe2x80x9d refers to compounds which have the same molecular formula but differ in the connectivity of the atoms. Accordingly, a xe2x80x9cregioselective processxe2x80x9d is one which favors the production of a particular regioisomer over others, e.g., the reaction produces a statistically significant majority of a certain regioisomer.
The term xe2x80x9creaction productxe2x80x9d means a compound which results from the reaction of the two substrate molecules. In general, the term xe2x80x9creaction productxe2x80x9d will be used herein to refer to a stable, isolable compound, and not to unstable intermediates or transition states.
The term xe2x80x9ccomplexxe2x80x9d as used herein and in the claims means a coordination compound formed by the union of one or more electronically rich molecules or atoms capable of independent existence with one or more electronically poor molecules or atoms, each of which is also capable of independent existence.
The term xe2x80x9csubstratexe2x80x9d is intended to mean a chemical compound which can react under the subject conditions to yield a product having at least one stereogenic center.
The term xe2x80x9ccatalytic amountxe2x80x9d is recognized in the art and means a substoichiometric amount of the catalyst relative to a reactant. As used herein, a catalytic amount means from 0.0001 to 90 mole percent catalyst relative to a reactant, more preferably from 0.001 to 50 mole percent, still more preferably from 0.01 to 10 mole percent, and even more preferably from 0.1 to 5 mole percent catalyst to reactant.
As discussed more fully below, the reactions contemplated in the present invention include reactions which are enantioselective, diastereoselective, and/or regioselective. An enantioselective reaction is a reaction which converts an achiral reactant to a chiral product enriched in one enantiomer. Enantioselectivity is generally quantified as xe2x80x9cenantiomeric excessxe2x80x9d (ee) defined as follows:
xe2x80x83% enantiomeric excess A (ee)=(% enantiomer A)xe2x88x92(% enantiomer B)
where A and B are the enantiomers formed. Additional terms that are used in conjunction with enatioselectivity include xe2x80x9coptical purityxe2x80x9d or xe2x80x9coptical activityxe2x80x9d. An enantioselective reaction yields a product with an e.e. greater than zero. Preferred enantioselective reactions yield a product with an e.e. greater than 20%, more preferably greater than 50%, even more preferably greater than 70%, and most preferably greater than 80%.
A diastereoselective reaction converts a reactant or reactants (which may be achiral, racemic, non-racemic or enantiomerically pure) to a product enriched in one diastereomer. If the chiral reactant is racemic, in the presence of a chiral, non-racemic reagent or catalyst, one reactant enantiomer may react more slowly than the other. This effect is termed a kinetic resolution, wherein the reactant enantiomers are resolved by differential reaction rate to yield an enantiomerically enriched product. Kinetic resolution is usually achieved by the use of sufficient reagent to react with only one reactant enantiomer (i.e. one-half mole of reagent per mole of racemic substrate). Examples of catalytic reactions which have been used for kinetic resolution of racemic reactants include the Sharpless epoxidation and the Noyori hydrogenation.
A regioselective reaction is a reaction which occurs preferentially at one reactive center rather than another reactive center. For example, a regioselective cycloaddition reaction of an unsyrmetrical 1,3,5-triene substrate would preferentially occur at one of the two 1,3-dienes contained therein.
The term xe2x80x9cnon-racemicxe2x80x9d means a preparation having greater than 50% of a desired stereoisomer, more preferably at least 75%. xe2x80x9cSubstantially non-racemicxe2x80x9d refers to preparations which have greater than 90% ee for a desired stereoisomer, more preferably greater than 95% ee.
The term xe2x80x9calkylxe2x80x9d refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and more preferably 20 of fewer. Likewise, preferred cycloalkyls have from 4-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
Moreover, the term alkyl as used throughout the specification and claims is intended to include both xe2x80x9cunsubstituted alkylsxe2x80x9d and xe2x80x9csubstituted alkylsxe2x80x9d, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, a halogen, a hydroxyl, an alkoxyl, a silyloxy, a carbonyl, and ester, a phosphoryl, an amine, an amide, an imine, a thiol, a thioether, a thioester, a sulfonyl, an amino, a nitro, or an organometallic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amines, imines, amides, phosphoryls (inlcuding phosphonates and phosphines), sulfonyls (inlcuding sulfates and sulfonates), and silyl groups, as well as ethers, thioethers, selenoethers, carbonyls (including ketones, aldehydes, carboxylates, and esters), xe2x80x94CF3, xe2x80x94CN and the like. Exemplary substitued alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, thioalkyls, aminoalkyls, carbonyl-substituted alkyls, CF3, CN, and the like.
The terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple bond, respectively.
Unless the number of carbons is otherwise specified, xe2x80x9clower alkylxe2x80x9d as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, xe2x80x9clower alkenylxe2x80x9d and xe2x80x9clower alkynylxe2x80x9d have similar chain lengths.
As used herein, the term xe2x80x9caminoxe2x80x9d means xe2x80x94NH2; the term xe2x80x9cnitroxe2x80x9d means xe2x80x94NO2; the term xe2x80x9chalogenxe2x80x9d designates xe2x80x94F, xe2x80x94Cl, xe2x80x94Br or xe2x80x94I; the term xe2x80x9cthiolxe2x80x9d means xe2x80x94SH; the term xe2x80x9chydroxylxe2x80x9d means xe2x80x94OH; the term xe2x80x9csulfonylxe2x80x9d means xe2x80x94SO2xe2x80x94; and the term xe2x80x9corganometallicxe2x80x9d refers to a metallic atom (such as mercury, zinc, lead, magnesium or lithium) or a metalloid (such as silicon, arsenic or selenium) which is bonded directly to a carbon atom, such as a diphenylmethylsilyl group.
Thus, the term xe2x80x9calkylaminexe2x80x9d as used herein means an alkyl group, as defined above, having a substituted or unsubstituted amine attached thereto. In exemplary embodiments, an xe2x80x9caminexe2x80x9d can be represented by the general formula: 
wherein R8 and R9 each independently represent a hydrogen, an alkyl, an alkenyl, xe2x80x94(CH2)mxe2x80x94R7, xe2x80x94C(xe2x95x90O)-alkyl, xe2x80x94C(xe2x95x90O)-alkenyl, xe2x80x94C(xe2x95x90O)-alkynyl, xe2x80x94C(xe2x95x90O)xe2x80x94(CH2)mxe2x80x94R7, or R8 and R9 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8.
Likewise, the term xe2x80x9calkylamidexe2x80x9d refers to an alkyl group having a substituted or unsubstituted amide group attached thereto. For instance, an xe2x80x9camidexe2x80x9d can be represented by the general formula: 
wherein R8 and R9 are as defined above.
The term xe2x80x9calkyliminexe2x80x9d refers to an alkyl group having a substituted or unsubstituted imine attached thereto. An xe2x80x9ciminexe2x80x9d can be represented by the general formula: 
wherein R8 is as described above.
The term xe2x80x9cthioalkylxe2x80x9d refers to an alkyl group, as defined above, having a sulfhydryl or thioether group attached thereto. In preferred embodiments, the xe2x80x9cthioetherxe2x80x9d moiety is represented by one of xe2x80x94S-alkyl, xe2x80x94S-alkenyl, xe2x80x94S-alkynyl, and xe2x80x94Sxe2x80x94(CH2)mxe2x80x94R7, wherein m and R7 are defined above.
The term xe2x80x9ccarbonyl-substituted alkylxe2x80x9d as used herein means an alkyl group, as defined above, having a substituted or unsubstituted carbonyl group attached thereto, and includes aldehydes, ketones, carboxylates and esters. In exemplary embodiments, the xe2x80x9ccarbonylxe2x80x9d moiety is represented by the general formula: 
wherein X is absent or represents an oxygen or a sulfur, and R10 represents a hydrogen, an alkyl, an alkenyl, or xe2x80x94(CH2)mxe2x80x94R7, where m and R7 are as defined above. Where X is an oxygen, the formula represents an xe2x80x9cesterxe2x80x9d. Where X is a sulfur, the formula represents a xe2x80x9cthioester.xe2x80x9d Where X is absent, and R10 is not hydrogen, the above formula represents a xe2x80x9cketonexe2x80x9d group. Where the oxygen atom of the above formula is replaced by sulfur, the formula represents a xe2x80x9cthiocarbonylxe2x80x9d group.
The terms xe2x80x9calkoxylxe2x80x9d or xe2x80x9calkoxyxe2x80x9d as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propoxy, tert-butoxy and the like. An xe2x80x9cetherxe2x80x9d is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl which renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of xe2x80x94O-alkyl, xe2x80x94O-alkenyl, xe2x80x94O-alkynyl, xe2x80x94Oxe2x80x94(CH2)mxe2x80x94R7, where m and R7 are described above.
Thus, the term xe2x80x9cphosphorylalkylxe2x80x9d as used herein means an alkyl group, as defined above, having a substituted or unsubstituted phosphoryl group attached thereto. A xe2x80x9cphosphorylxe2x80x9d can in general be represented by the formula: 
wherein Q1 represented S or O, and R46 represents hydrogen, a lower alkyl or an aryl. When used to substitute an alkyl, the phosphoryl group of the phosphorylalkyl can be represented by the general formula: 
wherein Q1 represented S or O, and each R46 indepedently represents hydrogen, a lower alkyl or an aryl, Q2 represents O, S or N.
The term xe2x80x9cmetalloalkylxe2x80x9d refers to an alkyl group, as defined above, having a substituted or unsubstituted organometallic group attached thereto. A xe2x80x9csilyl alkylxe2x80x9d is an alkyl having a substituted silicon attached thereto. In a preferred embodiment, the xe2x80x9csilylxe2x80x9d moiety which may be substituted on the alkyl can be represented by the general formula: 
wherein R10, Rxe2x80x210 and Rxe2x80x310 independently represent a hydrogen, an alkyl, an alkenyl, or xe2x80x94(CH2)mxe2x80x94R7, m and R7 being defined above.
Likewise, a xe2x80x9cselenoalkylxe2x80x9d refers to an alkyl group having a substituted seleno group attached thereto. Exemplary xe2x80x9cselenoethersxe2x80x9d which may be substituted on the alkyl are selected from one of xe2x80x94Se-alkyl, xe2x80x94Se-alkenyl, xe2x80x94Se-alkynyl, and xe2x80x94Sexe2x80x94(CH2)mxe2x80x94R7, m and R7 being defined above.
The term xe2x80x9csulfonatexe2x80x9d as used herein means a sulfonyl group, as defined above, attached to an alkyl or aryl group. Thus, in a preferred embodiment, a sulfonate has the structure: 
in which R11 is an alkyl or an aryl.
The term sulfate, as used herein, means a sulfonyl group, as defined above, attached to a hydroxy or alkoxy group. Thus, in a preferred embodiment, a sulfate has the structure: 
in which R40 and R41 are independently absent, a hydrogen, an alkyl, or an aryl. Furthermore, R40 and R41, taken together with the sulfonyl group and the oxygen atoms to which they are attached, may form a ring structure having from 5 to 10 members.
Analogous substitutions can be made to alkenyl and alkynyl groups to produce, for example, alkenylamines, alkynylamines, alkenylamides, alkynylamides, alkenylimines, alkynylimines, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls, alkenoxyls, alkynoxyls, metalloalkenyls and metalloalkynyls.
The term xe2x80x9carylxe2x80x9d as used herein includes 4-, 5-, 6- and 7-membered single-ring aromatic groups which may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as xe2x80x9caryl heterocyclexe2x80x9d. The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7, xe2x80x94CF3, xe2x80x94CN, or the like.
The terms xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic groupxe2x80x9d refer to 4 to 1 0-membered ring structures, more preferably 5 to 7 membered rings, which ring structures include one to four heteroatoms. Heterocyclic groups include pyrrolidine, oxolane, thiolane, imidazole, oxazole, piperidine, piperazine, morpholine. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7, xe2x80x94CF3, xe2x80x94CN, or the like.
The terms xe2x80x9cpolycyclexe2x80x9d or xe2x80x9cpolycyclic groupxe2x80x9d refer to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocycles) in which two or more carbons are common to two adjoining rings, e.g., the rings are xe2x80x9cfused ringsxe2x80x9d. Rings that are joined through non-adjacent atoms are termed xe2x80x9cbridgedxe2x80x9d rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7, xe2x80x94CF3, xe2x80x94CN, or the like.
The term xe2x80x9cheteroatomxe2x80x9d as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur, phosphorus and selenium.
A xe2x80x9cbridging substituentxe2x80x9d refers to a substitution at two (or more) sites on the core structure of the catalyst by the same (as opposed to identical) substituent so as to form a covalent bridge between the substitution sites. For example, a bridging substituent may be represented by the general formula or xe2x80x94R15xe2x80x94R16xe2x80x94R17xe2x80x94, wherein R15 and R17 each independently are absent or represent an alkyl, an alkenyl, or an alkynyl, preferably C1 to C10, and R16 is absent or represents an amine, an imine, an amide, a phosphoryl a carbonyl, a silyl, an oxygen, a sulfonyl, a sulfer, a selenium, or an ester. Exemplary bridging substituents are given by the xe2x80x9cpicnic basketxe2x80x9d forms of, for instance, the porphoryn catalysts described below.
For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. Also for purposes of this invention, the term xe2x80x9chydrocarbonxe2x80x9d is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom. In a broad aspect, the permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds which can be substituted or unsubstituted.
The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms, and dba represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and dibenzylideneacetone, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.
The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.
The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively. The terms triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, p-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
The phrase xe2x80x9cprotecting groupxe2x80x9d as used herein means temporary modifications of a potentially reactive functional group which protect it from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991).
As used herein, the term xe2x80x9csubstitutedxe2x80x9d is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described hereinabove. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
II. Catalyzed Reactions
In one aspect of the present invention there is provided a process for stereoselectively producing compounds with at least one stereogenic center. An advantage of this invention is that enantiomerically enriched products can be synthesized from achiral or racemic reactants. Another advantage is that yield losses associated with the production of an undesired enantiomer can be substantially reduced.
In general, the invention features a stereoselective cycloaddition process which comprises combining a diene, a dienophile, and at least a catalytic amount of a non-racemic, chiral catalyst of particular characteristics (as described below). The combination is maintained under conditions appropriate for the chiral catalyst to catalyze a stereoselective cycloaddition between the diene and dienophile. This reaction can be applied to enatioselective processes as well as diastereoselective processes. It may also be adapted for regioselective reactions. Examples of enantioselective reactions, kinetic resolution, and regioselective reactions which may be catalyzed according to the present invention follow.
In an exemplary embodiment, a Hetero-Diels-Alder reaction between an aldehyde and an electron-rich diene in the presence of a subject chiral, non-racemic catalyst yields a non-racemic dihydropyran product. This embodiment is an example of a diastereo- and enantioselective cycloaddition reaction. 
In another aspect of the invention, the hetero-Diels-Alder reaction occurs in a regioselective manner in the presence of a chiral, non-racemic catalyst. An illustrative example of a regioselective reaction is shown below. This exemplary embodiment of the subject invention involves diastereo-, regio- and enantioselective Hetero-Diels-Alder reactions exemplified by the thiene synthesis below. 
As shown below, the present invention also provides a method for stereoselective type 1 and type 2 intramolecular Hetero-Diels-Alder reactions.


In another illustrative embodiment, the present invention provides a method for the kinetic resolution of a racemic mixture of an aldehyde containing an xcex1-stereocenter. In the subject metal-mediated kinetic resolution process of a racemic aldehyde substrate, one enantiomer of the aldehyde can be recovered as unreacted substrate while the other is transformed to the desired product. This aspect of the invention provides methods of easily synthesizing functionalized non-racemic products from racemic starting materials. 
A second facet of kinetic resolution possible with the subject method involves resolution of a racemic diene substrate. In a preferred embodiment, racemic diene A will react with substoichiometric benzaldehyde (xcx9c0.5 equiv) in the presence of a subject chiral, non-racemic catalyst to yield dihydropyran B (de and ee greater than 0) and unreacted A (ee greater than 0). This type of kinetic resolution is rationalized by a presumed difference in the energies of the diastereomeric transition states for the reaction between the individual enantiomers of racemic A, and the chiral, non-racemic complex comprising benzaldehyde and the catalyst. This rationalization is not intended to be limiting in any way. 
As skilled artisans will recognize readily, the subject invention can be applied to 1,3-dienes which incorporate heteroatoms in their diene backbones. In a preferred embodiment, the 2-aza-1,3-diene shown below will react with acetaldehyde in the presence of a subject catalyst to provide stereoselectively the heterocyclic product. 
The overall reaction of an aldehyde with a 1,3-diene to generate a dihydropyranxe2x80x94the xe2x80x9cclassicalxe2x80x9d diene-aldehyde cyclocondensation reactionxe2x80x94has been shown to proceed via a stepwise, rather than a concerted, mechanism in certain cases (refer to the articles by Corey and Keck cited earlier for relevant examples and a discussion of this issue). Based on this literature, a preferred embodiment of the present invention involves the use of the instant chiral, non-racemic catalysts for the asymmetric aldol condensation of an aldehyde and a silyl enol ether. In additional prefered embodiments, the aldehyde substrate for these so-called xe2x80x9cMukaiyamaxe2x80x9d aldol condensations may be replaced with any carbonyl-containing compound including, but not limited to, ketones, esters, amides, imines and the like. 
The processes of this invention can provide optically active products with very high stereoselectivity (e.g., enantioselectivity or diasteroselectivity) or regioselectivity. In preferred embodiments of the subject enantioselective reactions, enantiomeric excesses of preferably greater than 50%, more preferably greater than 75% and most preferably greater than 90% can be obtained by the processes of this invention. Likewise, with respect to regioselective reactions, molar ratios for desired/undesired regioisomers of preferably greater than 5:1, more preferably greater than 10:1 and most preferably greater than 25:1 can be obtained by the processes of this invention. The processes of this invention can also be carried out at highly desirable reaction rates suitable for commercial use.
As is clear from the above discussion, the chiral products produced by the asymmetric synthesis processes of this invention can undergo further reaction(s) to afford desired derivatives thereof. Such permissible derivatization reactions can be carried out in accordance with conventional procedures known in the art. For example, potential derivatization reactions include epoxidation, ozonolysis, halogenation, hydrohalogenation, hydrogenation, esterification, oxidation of alcohols to aldehydes, ketones and/or carboxylate derivatives, N-alkylation of amides, addition of aldehydes to amides, nitrile reduction, acylation of alcohols by esters, acylation of amines and the like. To further illustrate, exemplary classes of pharmaceuticals which can be synthesized by a scheme including the subject stereoselective reaction are cardiovascular drugs, non-steroidal antiinflammatory drugs, central nervous system agents, and antihistaminics.
III. Catalysts
The catalysts employed in the subject method involve chiral complexes which provide controlled steric environments for asymmetric cycloadditon reactions. In general, catalysts intended by the present invention can be characterized in terms of a number of features. For instance, a salient aspect of each of the catalysts contemplated by the instant invention concerns the use of metalloligands which provide a rigid or semi-rigid environment near the catalytic site of the molecule. This feature, through imposition of structural rigidity on the chelated metal, can be used to establish selective approach of the substrate to the catalytic site and thereby induce stereoselectivity and/or regioselectivity in a cycloaddition reaction. Moreover, the ligand preferably places a restriction on the coordination sphere of the metal.
Another aspect of the catalyst concerns the selection of metal atoms for the catalyst. In general, any Lewis acidic metal may be used to form the catalyst, e.g., a main group metal, a metal selected from one of Groups 3-12 of the periodic table, or from the lanthanide series. In certain embodiments , the metal is a main group metal selected from the group consisting of Al, Ga, In, Si, Ge, and Sn. However, in preferred embodiments, the metal will be selected from the group of late transition metals, e.g. preferably from Groups 5-12, in order to provide metal centers which are coordinatively unsaturated and not in their highest oxidation state. For example, suitable metals include Co, Cr, Mn, V, Fe, Mo, W, Ru and Ni. Particularly preferred metals are from group 6, especially Cr(III).
A. Chiral Tetradentate Catalysts
Consistent with these desirable features, one class of particularly preferred chiral catalysts provide a chiral tetradentate ligand which coordinates a metal in a substantially square planar or square pyramidal geometry, though some distortion to these geometries is contemplated. Restated, these square geometries refer to tetradentate ligands in which the Lewis basic atoms lie substantially in the same plane, with the metal also in that plane (square planar), or above or below that plane (square pyramidal).
Preferred square tetradentate catalysts which may be employed in the subject reactions can be represented by the general formula 100: 
wherein Z1, Z2, Z3 and Z4 each represent a Lewis base, such as selected from the group consisting of nitrogen (e.g., imines, amines and amides), oxygen, phosphorus (e.g., phosphines or phosphinites), arsenic (arsines) and sulfur.
The C1 moiety (taken with Z1, Z3 and M) and the C2 moiety, (taken with Z2, Z4 and M) each, independently, form a heterocyclic ring. It will be understood that while the C1 and C2 structures depicted in the above formula may not formally be covalently closed rings for lack of a covalent bond with the metal M, for purposes of this disclosure, this and similar structures involving the metal catalyst atom M will nevertheless be referred to as heterocyclic rings, and substituents thereof will be referenced relative to heterocycle nomenclature (e.g., xe2x80x9cfused ringsxe2x80x9d or xe2x80x9cbridged ringsxe2x80x9d). In addition to substitutions at R1, R2, Rxe2x80x21 and Rxe2x80x22, the C1 and C2 rings can of course be substituted as appropriate at other ring positions, as illustrated by R40 and R41. Moreover, it will be appreciated that in certain embodiments two or more substituents of C1 can be covalently bonded to each other to provide a fused ring or bridged ring including the C1 ring atoms. Similar structures can be provided on the C2 ring.
Accordingly, in the illustrated structure 100, R1, R2, Rxe2x80x21 and Rxe2x80x22 each independently are absent, or represent some substitution, as permitted by valence requirements, of the Lewis basic atoms, which substitution may be with hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thio amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7; R40 and R41 each independently are absent, or represent one or more covalent substitutions of C1 and C2 with an organic or inorganic substituent permitted by valence requirements of the ring atom to which it is attached, or any two or more of the R1, R2, Rxe2x80x21, Rxe2x80x22 R40 and R41 substituents taken together can form a bridging substituent; with the proviso that at least one of R1, Rxe2x80x21 and R41 forms a bridging substituent with at least one of R2, Rxe2x80x22 and R40 in order to provide C1 and C2 as a tetradentate; R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle, and m is zero or an integer in the range of 1 to 8.
While the actual substituents of C1 and C2 can vary widely as necessary for a particular reaction scheme, one important proviso is that at least one substituent of C1 must form a covalent bond with at least one substituent of C2 in order to provide a tetradentate ligand which forms a square complex with M. That is, the ligand is a bridged cycle or polycycle which includes C1 and C2. Furthermore, in order for the catalyst to be chiral, e.g., to be capable of catalyzing stereoselective reactions, R1, R2, Rxe2x80x21, Rxe2x80x22 and other substituents of C1 and C2 are selected to provide at least one stereogenic center or an axis of dissymmetry, e.g. such that the ligand is asymmetric.
In the general structure 100, M represents a main group metal, a transition metal of Group 3-12 or the lanthide series of the periodic table, though preferably a metal ion which is not in its highest oxidation state. In the most preferred embodiments, M will be selected from the group of late transition metals,e.g., from the Group 5-12 metals. Even more preferably, M will be Cr(III). Moreover, the metal can be coordinated with a counteranion (as in the aged catalyst described below).
Exemplary catalysts of this class are comprised of ligands derived from, for example, salens, porphyrins, crown ethers, azacrown ethers, cyclams, phthalocyanines, and the like.
In a particularly preferred embodiment, the subject reactions use a chiral catalyst having a metal ion complexed via an imine of a chiral ligand, preferably a diimine bridge. Accordingly, such variants of structure 100 can be provided in embodiments wherein any one or more of the Lewis bases is an imine, with metallo-Schiff base forms of imines being highly preferred.
To further illustrate, a tetradentate catalyst useful in the subject method can be derived using chiral salen or salen-like ligands (hereinafter xe2x80x9csalenatesxe2x80x9d). The asymmetric metallosalenate catalysts offer a distinct advantage over many other chiral tetradentate catalyts, such as the metalloporphyrinates described infra, in that the salenate ligand can have stereogenic centers located just two bond lengths away from the metal. This proximity of the chiral centers to the reactive site can yield a high degree of stereoselectivity.
As disclosed herein, salen complexes are highly effective catalysts for the asymmetric hetero-Diels-Alder reaction and other cycloaddition reactions. This group of reactions is notable not only for its high enantioselectivity and for the utility of its products, but also for its remarkable efficiency as a catalytic process.
Moreover, the synthesis of chiral salenates is well characterized in the art, with more than 150 different chiral metallosalenates having been reported in the literature (see, for review, Collman et al. (1993) Science 261:1404-1411). These ligands are easily and inexpensively synthesized on large scale starting from readily available materials, as described in Larrow et al., J. Org Chem (1994) 59:1939-1942. Importantly, the general familiarity and ease of synthesis of metallosalenates permits the substituents to be readily varied in a systematic fashion in order to adjust the steric or electronic characteristics of the ligand. This feature makes possible the synthesis of ligands which are optimized for particular types of reaction or substrate. It has been found that such steric and electronic xe2x80x9ctuningxe2x80x9d (described infra) can have significant effects on the yield and e.e. of products formed in asymmetric reactions. In particular, the use of bulky blocking substituents is desirable to achieve high product e.e. in the asymmetric cycloadditions. Furthermore, the stereogenic moiety can easily be modified to improve enantioselectivity.
In general, the salenate ligands which are useful in the subject method as chiral metallosalenate catalysts can be characterized as two substituted xcex2-alkoxylimines which are linked to form a tetradentate ligand having at least one stereogenic center. In an exemplary embodiment, a metallosalenate catalyst useful in the asymmetric cycloaddition processes of the present invention can be represented by a metal complex with two substituted xcex2-alkoxylimines having the general formula: 
wherein
the substituents R1, R2, Y1, Y2, I1, X2, X3 and X4 each, independently, represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7,
or any two or more of the substituents taken together form a carbocycle or heterocycle having from 4 to 8 atoms in the ring structure, which ring structure may be a fused ring, as in the case of, for example, X1 and X2 forming a ring, or which ring may be a bridging ring, as in the case of R1 and R2, X2 and X4, or Y1 and X2 representing different ends of a single substituent,
with the proviso that at least one of R1, Y1, X1 and X2 is covalently bonded to at least one of R2, Y2, X3 and X4 to provide the xcex2-alkoxylimines as a tetradentate ligand;
R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle , or a polycycle;
m is zero or an integer in the range of 1 to 8;
M represents a metal; and
A represents a counterion;
wherein each of of the substituents of the xcex2-alkoxylimines, e.g., R1, R2, Y1, Y2, X1, X2, X3 and X4, are selected such that the catalyst is asymmetric.
The choice of each of R1, R2, Y1, Y2, X1, X2, X3 and X4 is also dependent on electronic and steric considerations, e.g., the tuning of the catalyst for a particular set of substrates, as well as the solvent system in which the reaction is to be carried out.
The chirality of the salenate ligand may be the result of the presence of one or more chiral atoms (e.g. carbon, sulfur, phosphorus, or other atoms capable of chirality), or may be the result of restricted rotation, helicity, molecular knotting or chiral metal complexation. In preferred embodiments, the chiral ligand has at least one chiral atom or is asymmetric due to restricted rotation. Further guidance regarding the particular choice of the substituents is set out herein.
In preferred embodiments, the choice of R1, R2, X1, X2, X3 and X4 yield a class of chiral catalysts which are represented by the general formula: 
in which the B1 moiety represents a diimine bridge, e.g. a bridging substituent which links the imino nitrogens of each xcex2-alkoxylimine, and preferably contains at least one chiral center of the salen ligand. For example, B1, taken together with the metal-coordinating imines of the xcex2-alkoxylimine, can represent the diimine of an alkyl, an alkenyl, an alkynyl, or the diimine of xe2x80x94R15xe2x80x94R16xe2x80x94R17xe2x80x94, wherein R15 and R17 each independently are absent or represent an alkyl, an alkenyl, or an alkynyl, and R16 is absent or represents an amine, an imine, an amide, a phosphonate, a phosphine, a carbonyl, a carboxyl, a silyl, an oxygen, a sulfur, a sulfonyl, a selenium, or an ester; each of B2 and B3 independently represent rings selected from a group consisting of cycloalkyls, cycloalkenyls, aryls, and heterocycles, which rings comprise from 4 to 8 atoms in a ring structure. The substituents R12, R13 and R14 each independently are absent, or represent one or more covalent substitutions of B1, B2 and B3 with halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7 (the substituent R12 occuring on one or more positions of xe2x80x94R15xe2x80x94R16xe2x80x94R17xe2x80x94); R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle , or a polycycle; m is zero or an integer in the range of 1 to 8. Moreover, any two or more of the R12, R13, R14, Y1 and Y2 substituted taken together can form bridging substituents to bridge the two xcex2-alkoxylimines and/or bridge different portions of the same xcex2-alkoxylimine. As above, in order to provide for a chiral catalyst, the choice of B2 and B3 (including their substituents) and/or the choice of substituents on B1 (e.g., B1 has a stereogenic center) is made to establish a chiral ligand. A represents a counterion.
In particular, as described in the appended examples, the salenate ligand can be derived from condensation of a substituted salicylaldehyde with a substituted diamine, preferably one stereoisomer of a chiral diamine, and then reacted with a desired metal to form a salen (N,Nxe2x80x2-bis(salicylideneamino)alkyl) metal complex. An exemplary reaction for generating the salen ligand is based on Zhang and Jacobsen (1991) J. Org Chem 56:2296-2298, and Jacobsen et al. PCT WO93/03838, and comprises: 
Utilizing this and other reaction schemes generally known in the art can provide a class of salens represented by the general formula: 
wherein each of the substituents R1, R2, R3, R4, R5, Y1, Y2, X1, X2, X3, X4, X5, X6, X7, and X8, independently, represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7;
any two or more of the substituents taken together may form a carbocyle or heterocycle having at least 4 atoms in the ring structure;
R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle;
m is zero or an integer in the range of 1 to 8; and
M represents a metal;
wherein
if R5 is absent, at least one of R1 and R2 is covalently bonded to at least one of R3 and R4; and the substituents of the salenate ligand are selected such that the salenate has at least one stereogenic center, e.g., is asymmetric. Moreover, the metal can be coordinated with a counterion (as in the aged catalyst described below).
With respect to generating a chiral ligand, it is important to note when selecting particular substituents that the salenate ligand has a potential catalytic site on both xe2x80x9csidesxe2x80x9d of the catalyst, e.g., relative to the plane of the four coordinating atoms of the ligand. Accordingly, when selecting the appropriate substituents for the xcex2-alkoxylimines in the above embodiments, it is important that either (1) both sides of the catalyst have stereogenic centers which effect identical stereoselectivity, or (2) the side having a stereogenic center of appropriate stereoselectivity is accessible while the other side has a blocking structure which substantially impairs approach to the metal atom on that side.
The first of these options is preferred. In other words, it is preferred to have at least one stereogenic center on each side of the salenate ligand, each having the same R/S configuration. For example, (R,R)-1,2-Diphenyl-1,2-bis(3-tert-butylsalicylideamino)ethane, described in the Examples, contains two stereogenic centers on the diimine bridge which give rise to identical stereoselective faces on each side of the catalyst. This bis-faced catalyst has the advantage of not being susceptible to xe2x80x9cleakagexe2x80x9d reactions because substrate approach, albeit constrained, may occur from either face without loss of selectivity.
In contrast, control of the reactivity of the mono-faced catalyst can be accomplished by sterically hindering substrate approach to the undesired face. For instance, the salenate (R)-2-phenyl-1,2-bis(3-tert-butylsalicylideamino)ethane, e.g., formula 106 wherein R1, R2 and R3 are protons, and R4 is a phenyl, has two non-equivalent faces in terms of enantioselectivity. Accordingly, derivatizing the salenate ligand with a group which blocks access to the xe2x80x9cfreexe2x80x9d face (e.g., the face having both a C1 and C2 proton of the diimine) can establish the ligand as a chiral catalyst with one enantiotopic face. For instance, a xe2x80x9cpicnic basketxe2x80x9d form of the ligand can be generated wherein the phenyl moiety of the diimine bridge is on the xe2x80x9cfrontsidexe2x80x9d of the catalyst, and X4 and X8 are covalently linked to form a bridge on the xe2x80x9cbacksidexe2x80x9d of the catalyst, which bridge substitution precludes access to the metal ion from the backside. Those skilled in the art will recognize other single- and double-sided embodiments (see, for example, Collman et al. (1993) Science 261:1404).
The synthesis schemes for metallosalenates which may be useful in the present method, or precursors thereof, can be adapted from the literature. For example, see Zhang et al. (1990) J Am Chem Soc112:2801; Zhang et al. (1991) J. Org Chem 56:2296; Jacobsen et al. (1991) J. Am Chem Soc 113:7063; Jacobsen et al. (1991) J. Am Chem Soc 113:6703; Lee et al. (1991) Tetrahedron Lett 32:5055; Jacobsen, E. N. In Catalytic Asymmetric Synthesis, Ojima, I., Ed., VCH: New York, 1993, chapter 4.2; E. N. Jacobsen PCT Publications WO81/14694 and WO93/03838; Larrow et al. (1994) J. Am Chem Soc 116:12129; Larrow et al. (1994) J. Org Chem 59:1939; Irie et al. (1990) Tetrahedron Lett 31:7345; Irie et al. (1991) Synlett 265; Irie et al. (1991) Tetrahedron Lett 32:1056; Irie et al. (1991) Tetrahedron Asymmetry 2:481; Katsuki et al. U.S. Pat. No. 5,352,814; Collman et al. (1993) Science 261:1404; Sasaki et al. (1994) Tetrahedron 50:11827; Palucki et al. (1992) Tetrahedron Lett 33:7111; and Srinivasan et al. (1986) J. Am Chem Soc 108:2309. Exemplary salenate ligands described in the above references are illustrated below, as well as in the appended examples [Ph=phenyl; tBu=tert-butyl]. 
In yet another embodiment of the subject method, the tetradentate catalyst of formula 100 is derived as a chiral tetradentate ligand represented, with the metal atom, by the general formula: 
in which
D1, D2, D3 and D4 each represent heterocycles, such as pyrrole, pyrrolidine, pyridine, piperidine, imidazole, pyrazine, or the like;
each R18 occurring in the structure represents a bridging substituent which links adjacent heterocycles, and preferably contains at least one stereogenic center of the ligand. For example, each R18, represents an alkyl, an alkenyl, an alkynyl, or xe2x80x94R15xe2x80x94R16xe2x80x94R17xe2x80x94, wherein R15 and R17 each independently are absent or represent an alkyl, an alkenyl, or an alkynyl, and R16 is absent or represents an amine, an imine, an amide, a phosphonate, a phosphine, a carbonyl, a carboxyl, a silyl, an oxygen, a sulfonyl, a sulfer, a selenium, or an ester;
each R19, independently, is absent or represents one or more substituents of the heterocycle to which it is attached, each substituent independently selected from the group consisting of halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, and xe2x80x94(CH2)mxe2x80x94R7;
any two or more of the R18 and R19 substituents may be covalently linked to form a bridge substitution;
R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle;
m is zero or an integer in the range of 1 to 8; and
M represents a metal,
wherein each of the substituents R18 and R19 are selected such that the catalyst is asymmetric, e.g., the catalyst contains at least one stereogenic center. The metal will generally be coordinated with a counterion (as in the aged catalyst described below).
In preferred embodiments, D1-D4 are substituted pyrroles, and the catalyst is a chiral porphyrin or porphyrin-like ligand (hereinafter xe2x80x9cporphyrinatesxe2x80x9d). As with the salenate ligands above, the synthesis of a vast number of porphyrinates has been reported in the literature. In general, most chiral porphyrins have been prepared in three ways. The most common approach involves attaching chiral units to preformed porphyrins such as amino- or hydroxy-substituted porphyrin derivatives (Groves et al. (1983) J. Am Chem Soc 105:5791). Alternatively, chiral substituents can be introduced at the porphyrin-forming stage by allowing chiral aldehydes to condense with pyrrole (O""Malley et al. (1989) J. Am Chem Soc 111:9116). Chiral porphyrins can also be prepared without the attachment of chiral groups. Similar to the bridged enantiotopic faces described for the salenates above, bridged porphyrinates can be generated by cross-linking adjacent and/or opposite pyrrolic positions and then separating the resulting mono-faced enantiomers with preparative HPLC using a chiral stationary phase (Konishi et al. (1992) J. Am Chem Soc 114:1313). Ultimately, as with the generation of chiral salenate ligands, the resulting porphyrinate must have no mirror plane in order to be considered chiral.
With reference to formula 100, it will be understood that metalloporphyrinate catalysts, in addition to being represented by formula 108, can be represented generally by the compound of formula 100 when each of Z1, Z2, Z3 and Z4 represent nitrogen, and C1 and C2 along with their substituents (including R1, Rxe2x80x21, R2, Rxe2x80x22) form four substituted pyrrole rings which include Z1, Z2, Z3 and Z4. To complete the square tetradentate ligand, each pyrrole ring is covalently attached to the two adjacent pyrrole rings.
In preferred embodiments, the metalloporphyrinate catalyst is represented by the general formula: 
in which
each R20 occurring in structure 110, independently, represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7;
each R19 and Rxe2x80x219 occurring in structure 110, independently, represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7;
any two R19 and Rxe2x80x219 substituents on the same pyrrole taken together may form a fused carbocycle or fused heterocycle having from 4 to 7 atoms in the ring structure;
any two or more of the R19, Rxe2x80x219 and R20 substituents may be covalently cross-linked to form a bridging substituent;
R7 represents an aryl, a cycloalkyl, a cycloalkenyl a heterocycle or a polycycle;
m is zero or an integer in the range of 1 to 8; and
M represents a metal,
wherein the substituents R19, Rxe2x80x219 and R20 are selected such that the catalysthas at least one stereogenic center, e.g., is asymmetric. The metal will generally be coordinated with a counterion (as in the aged catalyst described below).
As with the salenate ligands previously described, it is possible to sterically and electronically xe2x80x9ctunexe2x80x9d the porphyrin ligands to optimize reaction yield and e.e. Examples of suitable porphyrin ligands and synthesis schemes can be adapted from the art. For example, see Chang et al. (1979) J. Am Chem Soc 101:3413; Groves et al. (1989) J. Am Chem Soc 111:8537; Groves et al. (1990) J. Org Chem 55:3628; Mansuy et al. (1985) J Chem Soc Chem Commun p155; Nauta et al. (1991) J. Am Chem Soc 113:6865; Collman et al. (1993) J. Am Chem Soc 115:3834; and Kruper et al. (1995) J. Org Chem 60:725.
Still another class of the tetradentate catalysts represented by the general formula 100 and which are useful in the present asymmetric synthesis reactions can be represented by the formula: 
wherein
each of the substituents R1, R2, R3, R4, R5, R11, R12, R13 and R14, independent represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7;
any two or more of the substituents taken together may form a carbocycle or heterocycle having at least 4 atoms in the ring structure;
R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle;
m is zero or an integer in the range of 1 to 8; and
M represents a metal;
wherein
if R5 is absent, at least one of R1 and R2 is covalently bonded to at least one of R3 and R4, and
the substituents are selected such that the catalyst is asymmetric. The metal will generally be coordinated with a counterion (as in the aged catalyst described below).
Exemplary catalysts of formula 112 include: 
The synthesis of these and other related catalyst can be adapted from the literature. See, for example, Ozaki et al. (1990) J Chem Soc Perkin Trans2:353; Collins et al. (1986) J. Am Chem Soc 108:2088; and Brewer et al. (1988) J. Am Chem Soc 110:423.
In yet another embodiment, the tetradentate catalysts of formula 100 can be chosen from the class of azamacrocycle having a ligand represented by the general formula: 
wherein
R21 and R22 each represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7;
R20 is absent or represents one or more substituents of the pyridine to which it is attached, each substituent independently selected from the group consisting of halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7;
R23 and R24 each independently are absent or represent one or more substituents of the 1,3-diiminopropyl to which they are attached, each substituent independently selected from the group consisting of halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7;
or any two or more of the R20, R21, R22, R23 and R24 substituents are covalently linked to form a bridging substituent;
R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and
m is zero or an integer in the range of 1 to 8,
wherein the substituents R20, R21, R22, R23 and R24 are selected such that the catalyst is asymmetric.
One advantage to this class of tetradentate catalysts, like the salenates, derives from the fact that the ligand provides a metallo-shiff base complex. Furthermore, stereogenic centers can be sited within two bond lengths of the metal center. Exemplary ligands of formula 114 include: 
The synthesis of these and other embodiments of 114 are described in Prince et al. (1974) Inorg Chim Acta 9:51-54, and references cited therein.
Yet another class of tetradentate ligands of the subject method are the cyclams, such as represented by the general formula: 
in which each of the substituents Q8 indpendently, are absent or represent hydrogen or a lower alkyl, and each of R25, R26, R27 and R28, independently, represent one or more substituents on the ethyl or propyl diimine to which they are attached, which substituents are selected from the group of hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, and xe2x80x94(CH2)mxe2x80x94R7; or any two or more of the substituents taken together form a bridging substituent; R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle; and m is zero or an integer in the range of 1 to 8. Wherein the substituents are selected such that the catalyst is asymmetric. Exemplary embodiments and synthesis schemes for chiral cyclams useful in the present invention can be adapted from the art. See, for example, the Burrows et al. U.S. Pat. No. 5,126,464, Kimura et al. (1984) Inorg Chem 23:4181; Kimura et al. (1984) J. Am Chem Soc 106: 5497; Kushi et al. (1985) J Chem Soc Chem Commun 216; Machida et al. (1986) Inorg Chem 25:3461; Kimura et al. (1988) J. Am Chem Soc 110:3679; and Tabushi et al. (1977) Tetrahedron Lett 18:1049.
B. Chiral Tridentate Catalysts
In yet another embodiment of the subject method, the chiral catalyst which is provided in the reaction is from a class of chiral catalyst having a tridentate ligand which coordinates a transition metal in a substantially planar geometry, though as above some distortion to this geometry is contemplated. Accordingly, this planar geometry refers to tridentate ligands in which the Lewis basic atoms lie substantially in the same plane, with the metal also in that plane, or slightly above or below that plane.
Preferred planar tridentate catalysts which may be employed in the subject reactions can be represented by the general formula 140: 
wherein Z1, Z2, and Z3 each represent a Lewis base, such as selected from the group consisting of nitrogen, oxygen, phosphorus, arsenic and sulfur; the E1 moiety, taken with Z1, Z2 and M, and the E2 moiety, taken with Z2, Z3 and M, each, independently, form heterocycles; R80 and R81 each independently are absent, or represent one or more covalent substitutions of E1 and E2 with an organic or inorganic substituent permitted by valence requirements of the ring atom to which it is attached, or any two or more of the R80 and R81 substituents taken together form a bridging substituent; and M represents a transition metal, wherein each R1, R2, Rxe2x80x21, Rxe2x80x22 R80 and R81 substituents are selected to provide at least one stereogenic center in said tridentate ligand. In preferred embodiments, each R80 and R81 occuring in 140 independently represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7; R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. The metal will generally be coordinated with a counterion (as in the aged catalyst described below).
In certain embodiments, the catalyst complex comprises a tridentate ligand and is represented by general structure 160: 
wherein
Z represents N, P or As;
X represents independently for each occurrence O, S, Se or ZR;
M represents a metal ion and the requisite number of counterions;
R represents independently for each occurrence hydrogen, alkyl, aryl, halo, acyl or aralkyl; or taken together any two instances of R on adjacent carbons may represent an optionally substituted ring consisting of 3-8 backbone atoms inclusive; said ring being saturated, unsaturated or aromatic; and said ring may be fused to another optionally substituted ring;
Rxe2x80x2 represents independently for each occurrence hydrogen, alkyl, aryl, halo, acyl or aralkyl; or taken together the two instances of Rxe2x80x2 may represent an optionally substituted ring consisting of 3-8 backbone atoms inclusive; said ring being saturated, unsaturated or aromatic; and said ring may be fused to another optionally substituted ring; and
one or both of the carbons bearing an instance of Rxe2x80x2 may be asymmetric.
In certain embodiments, the catalyst complex is represented by general structure 160 and the associated definitions, wherein M represents Cr(III).
In certain embodiments, the catalyst complex is represented by general structure 160 and the associated definitions, wherein X represents O.
In certain embodiments, the catalyst complex is represented by general structure 160 and the associated definitions, wherein Z represents N.
In certain embodiments, the catalyst complex is represented by general structure 160 and the associated definitions, wherein X represents O; and Z represents N.
In certain embodiments, the catalyst complex is represented by general structure 160 and the associated definitions, wherein both of the carbons bearing an instance of Rxe2x80x2 are asymmetric.
In certain embodiments, the catalyst complex is represented by general structure 160 and the associated definitions, wherein X represents O; and both of the carbons bearing an instance of Rxe2x80x2 are asymmetric.
In certain embodiments, the catalyst complex is represented by general structure 160 and the associated definitions, wherein Z represents N; and both of the carbons bearing an instance of Rxe2x80x2 are asymmetric.
In certain embodiments, the catalyst complex is represented by general structure 160 and the associated definitions, wherein M represents Cr(III); X represents O; Z represents N; and both of the carbons bearing an instance of Rxe2x80x2 are asymmetric.
In certain embodiments, the catalyst complex comprises a tridentate ligand and is represented by general structure 162: 
wherein
X represents independently for each occurrence O, S, Se or ZR1;
Z represents independently for each occurrence N, P or As;
M represents a metal ion and the requisite number of counterions;
R1 represents independently for each occurrence hydrogen, alkyl or aryl;
R2 represents independently for each occurrence hydrogen, alkyl or aryl; and taken together the two instances of R2 may represent an optionally substituted ring consisting of 3-8 backbone atoms inclusive; said ring being saturated, unsaturated or aromatic; and said ring may be fused to another optionally substituted ring;
R3 may be absent or present between one and four times inclusive;
R3 represents independently for each occurrence alkyl, aryl, aralkyl, halo, acyl, sulfonyl, xe2x80x94(C(R1)2)mCOR1, xe2x80x94(C(R1)2)mCO2R1, xe2x80x94(C(R1)2)mNO2, xe2x80x94(C(R1)2)mS(O)nR1, xe2x80x94(C(R1)2)mOR1, xe2x80x94(C(R1)2)mN(R1)2;
n represents independently for each occurrence an integer in the range 0-3 inclusive;
m represents independently for each occurrence an integer in the range 0-8 inclusive; and
one or both of the carbons bearing an instance of R2 may be asymmetric.
In certain embodiments, the catalyst complex is represented by general structure 160 and the associated definitions, wherein M represents Cr(III).
In certain embodiments, the catalyst complex is represented by general structure 162 and the associated definitions, wherein Z represents N.
In certain embodiments, the catalyst complex is represented by general structure 162 and the associated definitions, wherein X represents O.
In certain embodiments, the catalyst complex is represented by general structure 162 and the associated definitions, wherein X represents O; and Z represents N.
In certain embodiments, the catalyst complex is represented by general structure 162 and the associated definitions, wherein both carbons bearing R2 are asymmetric.
In certain embodiments, the catalyst complex is represented by general structure 162 and the associated definitions, wherein X represents O; Z represents N; and both carbons bearing R2 are asymmetric.
In certain embodiments, the catalyst complex is represented by general structure 162 and the associated definitions, wherein R1 represents hydrogen.
In certain embodiments, the catalyst complex is represented by general structure 162 and the associated definitions, wherein X represents O; Z represents N; both carbons bearing R2 are asymmetric; and R1 represents hydrogen.
In certain embodiments, the catalyst complex is represented by general structure 162 and the associated definitions, wherein M represents Cr(III); X represents O; Z represents N; both carbons bearing R2 are asymmetric; R1 represents hydrogen; and R3 is present once or twice and represents alkyl.
For example, a chiral tridentate catalyst useful in the subject stereoselective reactions can have a ligand represented by the general formula: 
wherein each of R100, R102 and R104 each independently are absent, or represent one or more covalent substitutions of heterocycle to which it is attached, or any two or more of the substituents taken together form a bridging substituent; wherein each R100, R102 and R104 substituents, if present, can be selected from the group consisting of halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7; R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. Again, the substitution of 142 is intended to provide at least one stereogenic center in the tridentate ligand. Exemplary embodiments of the 2,2xe2x80x2:6xe2x80x2,2xe2x80x3-terpyridine ligands 142 and their synthesis can be adapted from, for example, Potts et al. (1987) J. Am Chem Soc 109:3961; Hadda et al. (1988) Polyhedron 7:575; Potts et al. (1985) Org Synth 66:189; and Constable et al. (1988) Inorg Chim Acta 141:201. Exemplary 2,6-bis(N-pyrazolyl)pyridine ligands 144 can be adapted from, for example, Steel et al. (1983) Inorg Chem 22:1488; and Jameson et al. (1990) J. Org Chem 55:4992.
Yet another class of planar tridentate catalyst useful in the subject stereoselective reactions can have a ligand represented by the general formula: 
wherein each of R106, R108 and R110 can be selected from the group consisting of hydrogens, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7; R112 is absent or represent one or more covalent substitutions of the heterocycle to which it is attached; or any two or more of the R106, R108, R110 and R112 substituents taken together form a bridging substituent; R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. The choice of substitution of 146 is intended to enhance its chirality. Exemplary embodiments of the salicylaldehyde-derived ligands 146 and their synthesis can be adapted from, for example, Desimoni et al. (1992) Gazzetta Chimica Italiana 122:269.
In a preferred embodiment, the tridentate ligand is given by the general formula 150 
wherein R106 represents a hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, ester, or xe2x80x94(CH2)mxe2x80x94R7; and each of R112 and Rxe2x80x2112 is absent or represent one or more covalent substitutions of the heterocycle to which it is attached, such as designated for R106; R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. For example, as described in the appended examples, a preferred salicylaldehyde-derived ligand is given by the general formula 152 
each R112 being independently selected.
Still another class of planar tridentate catalyst useful in the subject stereoselective reactions can have a ligand represented by the general formula: 
wherein R100 is as described above, and each R116 and R114 can be selected from the group consisting of hydrogens, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R7; or any two or more of the substituents taken together form a bridging substituent; R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. The choice of substitution of 148 is intended to provide at least one stereogenic center in the tridentate ligand. Exemplary embodiments of the salicylaldehyde-derived ligands 148 and their synthesis can be adapted from, for example, Marangoni et al. (1993) Polyhedron 12:1669.
C. Tuning the Catalysts
The ligand substituents are chosen to optimize the selectivity of reaction and the catalyst stability. The exact mechanism of action of the metallosalenate-catalyzed cycladdition reactions has not yet been precisely elucidated. However, the need for stereoselective nonbonded interactions between the substrate and catalyst is a feature of this and other chiral planar catalysts of the subject reaction. While not wishing to be bound by any particular theory, it is believed that the present cycloaddition reactions involve two factors largely responsible for induction of asymmetry by formation of stereospecific nonbonded pairs of catalyst and substrate, namely, steric and electronic interactions between a substrate and the ligand of the chiral catalyst. In general, xe2x80x9ctuningxe2x80x9d refers altering the steric bulk of the ligand to limit the approach of the substrate, utilizing steric repulsions between the substrate and ligand substituents, and altering the electronic characteristics of the ligand to influence electronic interactions between the substrate and the ligand, as well as the rate and mechanism of the catalyzed reaction. For instance, the choice of appropriate substituents as xe2x80x9cblocking groupsxe2x80x9d enforces certain approach geometries and disfavors others.
Furthermore, the choice of substituent may also affect catalyst stability; in general, bulkier substituents are found to provide higher catalyst turnover numbers. It has been found that for the asymmetric epoxidation of olefins by Mn(salen) complexes, t-butyl groups (or other tertiary groups) are suitable bulky moieties for optimizing stereoselectivity and increasing catalyst turnover.
A preferred embodiment for each of the embodiments described above provides a catalyst having a molecular weight less than 10,000 g/m (a.m.u.), more preferably less than 5000 g/m, and even more preferably less than 2500 g/m. In another preferred embodiment, none of the substituents of the core ligand, or any molecule coordinated to the metal in addition to the ligand, have molecular weights in excess 1000 g/m, more preferably they are less than 500 g/m, and even more preferably, are less than 250 g/m. The choice of substituent on the ligand can also be used to influence the solubility of the catalyst in a particular solvent system.
As mentioned briefly above, the choice of ligand substituents can also affect the electronic properties of the catalyst. Substitution of the ligand with electron-rich (electron-donating) moieties (including, for example, alkoxy or amino groups) increases the electron density of the ligand and at the metal center. Conversely, electron-withdrawing moieties (for example, chloro or trifluoromethyl) on the ligand result in lower electron density of the ligand and metal center. The electron density of the ligand is important due to the possibility of interactions (such as r-stacking) with the substrate (see, e.g., Hamada et al. Tetrahedron (1994) 50:11827). The electron density at the metal center may influence the Lewis acidity of the metal. Choice of appropriate substituents thus makes possible the xe2x80x9ctuningxe2x80x9d of the reaction rate and the stereoselectivity of the reaction.
IV. Substrates
Substrates which are useful in the present invention may be determined by the skilled artisan according to several criteria. In general, suitable substrates will have one or more of the following properties: 1) They will be capable of participating in a cycloaddition reaction under the subject conditions; 2) Said cycloaddition reaction will yield a useful product; 3) They will not react at undesired functionalities; 4) They will react at least partly through a mechanism catalyzed by the chiral catalyst; 5) They will not undergo significant further undesired reaction after reacting in the desired sense; 6) They will not substantially react with or degrade the catalyst, e.g. at a rate greater than conversion of the substrate. It will be understood that while undesirable side reactions (such as catalyst degradation) may occur, the rates of such reactions can be manipulated through the selection of reactants and conditions; these manipulations will render the undesired side reactions slow in comparison with the rate of the desired reaction(s).
In certain embodiments, the reactive substrates may be contained in the same molecule, thereby resulting in an intramolecular cycloaddition reaction.
As discussed above, a wide variety of substrates are useful in the methods of the present invention. The choice of substrates will depend on factors such as the desired product, and the appropriate substrates will be apparent to the skilled artisan. It will be understood that the substrates preferably will not contain any interfering functionalities. In general, appropriate substrates will contain either a reactive xcfx80-bond or a reactive 1,3-diene moiety.
V. Reaction Conditions
The asymmetric reactions of the present invention may be performed under a wide range of conditions, though it will be understood that the solvents and temperature ranges recited herein are not limitative and only correspond to a preferred mode of the process of the invention.
In general, it will be desirable that reactions are run using mild conditions which will not adversely affect the substrate, the catalyst, or the product. For example, the reaction temperature influences the speed of the reaction, as well as the stability of the reactants and catalyst. The reactions will usually be run at temperatures in the range of xe2x88x9278xc2x0 C. to 100xc2x0 C., more preferably in the range xe2x88x9220xc2x0 C. to 50xc2x0 C. and still more preferably in the range xe2x88x9220xc2x0 C. to 25xc2x0 C.
In general, the asymmetric synthesis reactions of the present invention are carried out in a liquid reaction medium. The reactions may be run without addition of solvent (see Example 8, infra). Alternatively, the reactions may be run in an inert solvent, preferably one in which the reaction ingredients, including the catalyst, are substantially soluble. Suitable solvents include ethers such as diethyl ether, 1,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran and the like; halogenated solvents such as chloroform, dichloromethane, dichloroethane, chlorobenzene, and the like; aliphatic or aromatic hydrocarbon solvents such as benzene, toluene, hexane, pentane and the like; esters and ketones such as ethyl acetate, acetone, and 2-butanone; polar aprotic solvents such as acetonitrile, dimethylsulfoxide, dimethylformamide and the like; or combinations of two or more solvents. Furthermore, in certain embodiments it may be advantageous to employ a solvent which is not inert to the substrate under the conditions employed. In certain embodiments, ethereal solvents are preferred.
The invention also contemplates reaction in a biphasic mixture of solvents, in an emulsion or suspension, or reaction in a lipid vesicle or bilayer. In certain embodiments, it may be preferred to perform the catalyzed reactions in the solid phase.
In some preferred embodiments, the reaction may be carried out under an atmosphere of a reactive gas. The partial pressure of the reactive gas may be from 0.1 to 1000 atmospheres, more preferably from 0.5 to 100 atm, and most preferably from about 1 to about 10 atm. In certain embodiments it is preferable to perform the reactions under an atmosphere of an inert gas such as nitrogen or argon.
The asymmetric synthesis processes of the present invention can be conducted in continuous, semi-continuous or batch fashion and may involve a liquid recycle and/or gas recycle operation as desired. The processes of this invention are preferably conducted in batch fashion. Likewise, the manner or order of addition of the reaction ingredients, catalyst and solvent are also not critical and may be accomplished in any conventional fashion.
The reaction can be conducted in a single reaction zone or in a plurality of reaction zones, in series or in parallel or it may be conducted batchwise or continuously in an elongated tubular zone or series of such zones. The materials of construction employed should be inert to the starting materials during the reaction and the fabrication of the equipment should be able to withstand the reaction temperatures and pressures. Means to introduce and/or adjust the quantity of starting materials or ingredients introduced batchwise or continuously into the reaction zone during the course of the reaction can be conveniently utilized in the processes especially to maintain the desired molar ratio of the starting materials. The reaction steps may be effected by the incremental addition of one of the starting materials to the other. Also, the reaction steps can be combined by the joint addition of the starting materials to the optically active metal-ligand complex catalyst. When complete conversion is not desired or not obtainable, the starting materials can be separated from the product and then recycled back into the reaction zone.
The processes may be conducted in either glass lined, stainless steel or similar type reaction equipment. The reaction zone may be fitted with one or more internal and/or external heat exchanger(s) in order to control undue temperature fluctuations, or to prevent any possible xe2x80x9crunawayxe2x80x9d reaction temperatures.
Furthermore, the chiral catalyst can be immobilized or incorporated into a polymer or other insoluble matrix by, for example, derivativation with one or more of substituents of the ligand. The immobilized ligands can be complexed with the desired metal to form the chiral metallocatalyst. The catalyst, particularly the xe2x80x9cagedxe2x80x9d catalyst described herein (Example 8, infra), is easily recovered after the reaction as, for instance, by filtration or centrifugation.